A number of C-glycosides are found in nature and these compounds have been the target of partial or total synthesis. Further, a series of therapeutically effective β-C-arylglucosides (canagliflozin (Ia), dapagliflozin (Ib), ipragliflozin (Ic) and empagliflozin (Id)) that are Sodium-coupled GLucose co-Transporter 2 (SGLT2) inhibitors have recently received marketing approval for the treatment of diabetes active pharmaceutical ingredient. C-Nucleosides are also suitable candidates for use as building blocks of oligonucleotides, for the preparation of natural products and their biologically active derivatives.
While there are different approaches to the preparation of C-arylglycosides, highly efficient methods for their preparation have not yet been realized for certain functionalized β-C-arylglucosides. Synthetic approaches for the preparation of β-C-arylglucosides using organometallics are known in the art, and may include 1,2-addition reactions (see Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53, 752-753 and Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610-612, for example).
Ineffeciencies known in the art for preparing β-C-arylglucosides include (1) a lack of stereoselectivity during formation of the desired β-anomer of the C-arylglucoside, (2) poor redox economy due to oxidation and reduction reaction steps being required to change the oxidation state of C1, or of C1 and C2, of the carbohydrate moiety, (3) relatively long synthetic routes, (4) the use of toxic metals such as palladium, and/or (5) atom uneconomic protection of hydroxyl groups.
There is a need for a novel, efficient and stereoselective process for the preparation of β-C-arylglucosides.